This study aimed to explore the impact of flooding stress on osmotic adjustment substance contents and the waterlogging resistance acclimation mechanism of Zanthoxylum armatum upon coupling of water and fertilizer management. A pot experiment with four factors and a four-level orthogonal design, including soil moisture (20%, 40%, 60%, and 80% field water capacity (FWC)) and nitrogen (N 0, 75, 150, and 300 kg/hm2), phosphorous (including P2O5 0, 30, 60, and 120 kg/hm2), and potassium (K2O 0, 75, 150, and 300 kg/hm2) fertilizers, was conducted to study the leaf membrane permeability, osmotic material content, and appearance of phenotypes during waterlogging for 0 d, 1 d, 3 d, and 5 d and plant recovery after drainage. A subordinate function was applied to comprehensively evaluate the impact of water and fertilizer on the waterlogging resistance of seedlings. The results showed that T12 (N300P30K0 + 60% FWC) treatment caused the least damage to leaves and resulted in the highest resistance to waterlogging. After drainage, the seedlings of T8 (N300P60K75 + 40% FWC), T9 (N0P60K300 + 60% FWC), T10 (N75P120K150 + 60% FWC), T11 (N150P0K75 + 60% FWC) and T12 (N300P30K0 + 60% FWC) treatments could return to normal growth levels, while the others died. During waterlogging stress, free proline content and relative conductivity of leaves in all treatments were increased, leaf soluble sugar and soluble protein contents increased until they reached maximum values and then declined, and the maximum values were observed on the 3rd day in case of all treatments. The optimal combination of water and fertilizer for protection against waterlogging stress included 60.8% FWC, 243 kg/hm2 N, 97 kg/hm2 P2O5, and 243 kg/hm2 K2O, which was determined by a comprehensive evaluation of waterlogging resistance. The results suggest that appropriate soil moisture and N, P, and K fertilizer application are important for promoting growth and enhancing stress resistance of Z. armatum seedlings.